'Reading the Mind in the Eyes': an fMRI study of adolescents with autism and their siblings.

BACKGROUND: Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the 'Reading the Mind in the Eyes' task (the Eyes task) have been identified in individuals with ASC in previous studies. METHOD: Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC-control and sibling-control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC-control and sibling-control differences across multiple thresholds. RESULTS: Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups. CONCLUSIONS: Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.

Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence.

During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group's developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity-second diffusion eigenvalue-in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism.

Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents.

Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives.

A novel functional brain imaging endophenotype of autism: the neural response to facial expression of emotion.

Siblings of individuals with autism have over 20 times the population risk of autism. Evidence of comparable, but less marked, cognitive and social communication deficits in siblings suggests a role for these traits in the search for biomarkers of familial risk. However, no neuroimaging biomarkers of familial risk have been identified to date. Here we show, for the first time, that the neural response to facial expression of emotion differs between unaffected siblings and healthy controls with no family history of autism. Strikingly, the functional magnetic resonance imaging (fMRI) response to happy versus neutral faces was significantly reduced in unaffected siblings compared with controls within a number of brain areas implicated in empathy and face processing. The response in unaffected siblings did not differ significantly from the response in autism. Furthermore, investigation of the response to faces versus fixation crosses suggested that, within the context of this study, an atypical response specifically to happy faces, rather than to faces in general, accounts for the observed sibling versus controls difference and is a clear biomarker of familial risk. Our findings suggest that an atypical implicit response to facial expression of emotion may form the basis of impaired emotional reactivity in autism and in the broader autism phenotype in relatives. These results demonstrate that the fMRI response to facial expression of emotion is a candidate neuroimaging endophenotype for autism, and may offer far-reaching insights into the etiology of autism.